T cells (or T lymphocytes) are found widely distributed within tissues and the tumour environment. T cells are distinguished from other lymphocytes by the presence of T cell receptors (TCRs) on the cell surface. The TCR is a multi-subunit transmembrane complex that mediates the antigen-specific activation of T cells. The TCR confers antigen specificity on the T cell, by recognising an antigen peptide ligand that is presented on the target cell by a major histocompatibility complex (MHC) molecule.
Although peptides derived from altered or mutated proteins in tumour target cells can be recognised as foreign by T cells expressing specific TCRs, many antigens on tumour cells are simply upregulated or overexpressed (so called self-antigens) and do not induce a functional T cell response. Therefore, studies have focussed on identifying target tumour antigens which are expressed, or highly expressed, in the malignant but not the normal cell type. Examples of such targets include the cancer/testis (CT) antigen NY-ESO-1, which is expressed in a wide array of human cancers but shows restricted expression in normal tissues (Chen Y-T et al. Proc Natl Acad Sci USA. 1997; 94(5): 1914-1918), and the MAGE-A family of CT antigens which are expressed in a very limited number of healthy tissues (Scanlan M. J. et al. Immunol Rev. 2002; 188:22-32).
Identification of such antigens has promoted the development of targeted T cell-based immunotherapy, which has the potential to provide specific and effective cancer therapy (Ho, W. Y. et al. Cancer Cell 2003; 3:1318-1328; Morris, E. C. et al. Clin. Exp. Immunol. 2003; 131:1-7; Rosenberg, S. A. Nature 2001; 411:380-384; Boon, T. and van der Bruggen P. J. Exp. Med. 1996; 183:725-729).
However, the microenvironment of a tumour is often immunosuppressive and prevents the successful immunotherapy of cancer (Rabinovich G. A. et al. Annu Rev Immunol. 2007; 25:267-296). Extracellular adenosine is a known inhibitor of immune function. High levels of adenosine in tumours have been found to play a significant role in the evasion of anti-tumour immune responses (Blay J. et al. Cancer Res. 1997; 57:2602-2605; Ohta A. et al. Proc Natl Acad Sci USA. 2006; 103:13132-13137). The adenosine-rich environment in tumours may induce T cell anergy (Zarek P. E. et al. Blood 2008; 111:251-259; Ohta A. et al. J Immunol. 2009; 183:5487-5493), increase production of immunosuppressive cytokines (e.g., TGF-beta, IL-10) (Zarek P. E. et al. supra; Nowak M. et al. Eur J Immunol. 2010; 40:682-687), and discourage cellular immune responses by targeting antigen-presenting cells (Hasko G. et al. Faseb J. 2000; 1 4:2065-2074; Panther E. et al. Blood 2003; 101:3985-3990).
Prostaglandin E2 (PGE2) is also known to be an inhibitor of immune functions and has been widely demonstrated to suppress both innate and antigen-specific immunity (Phipps R. P. et al. Immunol Today. 1991; 12:349-352; Harris S. G. et al. Trends Immunol. 2002; 23:144-150).
T cell-based immunotherapies which are more able to cope with the hostile tumour environment would be useful in providing more effective cancer therapy.